Adduct, endo

Figure 1.2. Endo and exo pathway for the Diels-Alder reaction of cyclopentadiene with methyl vinyl ketone. As was first noticed by Berson, the polarity of the endo activated complex exceeds that of the exo counterpart due to alignment of the dipole moments of the diene and the dienophile K The symmetry-allowed secondary orbital interaction that is only possible in the endo activated complex is usually invoked as an explanation for the preference for endo adduct exhibited by most Diels-Alder reactions.

Likewise, Grieco, while working with amphiphile-like reactants, observed an enhanced preference for endo-adduct in aqueous solutions, which he attributed to orientational effects within the micelles that were presumed to be present in the reaction mixture ". Although under the conditions used by Grieco, the presence of aggregates cannot be excluded, other studies have clearly demonstrated that micelle formation is not the reason for the improved selectivities . Micellar a peg tes even tend to diminish the preference for endo adduct. ... 

In conclusion, the special influence of water on the endo-exo selectivity seems to be a result of the fact that this solvent combines in it three characteristics that all favour formation of the endo adduct (1) water is a strong hydrogen bond donor, (2) water is polar and (3) water induces hydrophobic interactions. 

Vinylboranes are interesting dienophiles in the Diels-Alder reaction. Alkenylboronic esters show moderate reactivity and give mixtures of exo and endo adducts with cyclopentadiene and 1,3-cyclohexadiene (441). Dichloroalkenylboranes are more reactive and dialkylalkenylboranes react even at room temperature (442—444). Dialkylalkenylboranes are omniphilic dienophiles insensitive to diene substitution (444). In situ formation of vinyl-boranes by transmetaHation of bromodialkylboranes with vinyl tri alkyl tin compounds makes possible a one-pot reaction, avoiding isolation of the intermediate vinylboranes (443). Other cycloadditions of alkenyl- and alkynylboranes are known (445). 

The success of the cycloaddition reaction of maleic anhydride varies gready depending on which heterocyclic diene is used. The cycloaddition of maleic anhydride to furan [110-00-9] occurs ia a few seconds under ambient conditions (42,43). Although the endo adduct (14) is favored kiaeticaHy, the exo adduct (13) is isolated. 

Endo adducts are usually favored by iateractions between the double bonds of the diene and the carbonyl groups of the dienophile. As was mentioned ia the section on alkylation, the reaction of pyrrole compounds and maleic anhydride results ia a substitution at the 2-position of the pyrrole ring (34,44). Thiophene [110-02-1] forms a cycloaddition adduct with maleic anhydride but only under severe pressures and around 100°C (45). Addition of electron-withdrawiag substituents about the double bond of maleic anhydride increases rates of cycloaddition. Both a-(carbomethoxy)maleic anhydride [69327-00-0] and a-(phenylsulfonyl) maleic anhydride [120789-76-6] react with 1,3-dienes, styrenes, and vinyl ethers much faster than tetracyanoethylene [670-54-2] (46). 

The diene addition is stereochemically specific (22). Although two stereoisomers are possible, the endo and the exo forms, in the addition of maleic anhydride to CPD the endo adduct is the exclusive product (23). 

There are probably several factors which contribute to determining the endo exo ratio in any specific case. These include steric effects, dipole-dipole interactions, and London dispersion forces. MO interpretations emphasize secondary orbital interactions between the It orbitals on the dienophile substituent(s) and the developing 7t bond between C-2 and C-3 of the diene. There are quite a few exceptions to the Alder rule, and in most cases the preference for the endo isomer is relatively modest. For example, whereas cyclopentadiene reacts with methyl acrylate in decalin solution to give mainly the endo adduct (75%), the ratio is solvent-sensitive and ranges up to 90% endo in methanol. When a methyl substituent is added to the dienophile (methyl methacrylate), the exo product predominates. ... 

Display space-filling models of endo adduct and exo adduct. Which appears to be the less crowded Identify specific interactions which disfavor the higher-energy adduct. Next, compare energies of the two adducts. Which is the more stable Were the reaction under thermodynamic control, which would be the major product and what would be the ratio of major to minor products Use equation (1). 

Are the kinetic and thermodynamic products the same If not, describe conditions which will favor the endo adduct. The exo adduct. 

Person postulated that the transition state giving rise to the endo adduct should be more polar than that giving rise to the exo adduct, and so polar solvents should... 

A high endo selectivity is observed in the reaction of (phenylsulfonyl)allene (112) with furan (157) (equation 113)108. The endo adduct 158 can be readily transformed into highly substituted cyclohexenol 160 upon treatment with n-butyllithium after hydrogenation of the ring double bond (equation 114)108. 

The reaction of chiral sulfones 161, derived from (lS)-( + )-10-camphorsulfonyl chloride, with cyclopentadiene gives predominantly the endo adduct in a diastereomeric ratio of 91 9 from which one diastereomer 162 can be isolated in pure form by recrystallization (equation 115)109. 

The first studies on cation-radical Diels-Alder reactions were undertaken by Bauld in 1981 who showed [33a] the powerful catalytic effect of aminium cation radical salts on certain Diels-Alder cycloadditions. For example, the reaction of 1,3-cyclohexadiene with trans, iraw5-2,4-hexadiene in the presence of Ar3N is complete in 1 h and gives only the endo adduct (Equation 1.14) [33]. 

The exo addition mode is expected to be preferred because it suffers fewer steric repulsive interactions than the endo approach however, the endo adduct is usually the major product because of stabilizing secondary orbital interactions in the transition state (Scheme 1.10). The endo preference is known as Alder s rule. A typical example is the reaction of cyclopentadiene with maleic anhydride which, at room temperature, gives the endo adduct which is then converted at... 

Commercial chromatography silica gel promotes effectual Diels-Alder cycloaddition of optically active pyrone lactate ester (5) with benzyl vinyl ether (6), affording the endo adduct 7 in an approximately 4 1 mixture of diastereoisomers [16] (Equation 4.1). 

The thermal reaction of cyclopentadiene (1) with maleic anhydride gives 98 % kinetically favoured endo adduct, unless the mixture is heated for a long time [44]. Under photolysis conditions and in the presence of triethylamine in dry ethanol, a reversed selectivity was found [45] (Scheme 4.13). 

The photo-induced exo selectivity was observed in other classic Diels-Alder reactions. Data relating to some exo adducts obtained by reacting cyclopentadiene or cyclohexadiene with 2-methyl-1,4-benzoquinone, 5-hydroxynaphtho-quinone, 4-cyclopentene-l,3-dione and maleic anhydride are given in Scheme 4.13. The presence and amount of EtsN plays a decisive role in reversing the endo selectivity. The possibility that the prevalence of exo adduct is due to isomerization of endo adduct under photolytic conditions was rejected by control experiments, at least for less reactive dienophiles. 

The intramolecular /zetero-Diels-Alder reactions of 4-O-protected acyl-nitroso compounds 81, generated in situ from hydroxamic acids 80 by periodate oxidation, were investigated under various conditions in order to obtain the best endo/exo ratio of adducts 82 and 83 [65h] (Table 4.15). The endo adducts are key intermediates for the synthesis of optically active swainsonine [66a] and pumiliotoxin [66b]. The use of CDs in aqueous medium improves the reaction yield and selectivity with respect to organic solvents. 

In contrast, the trimer 89 with ethyne and butadiyne links stabilizes the thermodynamically disfavored endo transition state, and the endo adduct 86 is rapidly and almost exclusively formed. 

The cycloadditions of cyclopentadiene 1 and its spiro-derivatives 109 and 110 with quinones 52, 111 and 112 (Scheme 4.20), carried out in water at 30 °C in the presence of 0.5% mol. of cetyltrimethylammonium bromide (CTAB), gave the endo adduct in about 3 h with good yield [72b]. With respect to the thermal Diels-Alder reaction, the great reaction rate enhancement in micellar medium (Scheme 4.20) can be ascribed to the increased concentration of the reactants in the micellar pseudophase where they are also more ordered. 

Base-catalyzed Diels-Alder reactions are rare (Section 1.4). A recent example is the reaction of 3-hydroxy-2-pyrone (145) with chiral N-acryloyl oxazolidones 146 that uses cinchona alkaloid as an optically active base catalyst [97] (Table 4.25). Only endo adducts were obtained with the more reactive dienophile 146 (R = H), the best diastereoselectivity and yields being obtained with an i-Pr0H/H20 ratio of 95 5. The reaction of 146 (R = Me) is very slow, and a good adduct yield was only obtained when the reaction was carried out in bulky alcohols such as t-amyl alcohol and t-butanol. 

Diels-Alder reaction of dienophiles, N-allylic enamides and a,/l-unsaturated lactam derivatives with open chain and inner ring dienes is promoted by iodine [98]. Thus the cycloaddition of N-benzyl-N-methallyl acrylamide 147 with cyclo-pentadiene (1) proceeds smoothly in DMF at —78 °C in the presence of I2 (2 eq.) to give a prevalence of endo adduct l Vd) in 88% yield (Equation 4.17). 

The different ratios of 52/53 produced by cycloadditions performed at atmospheric and high pressure, and the forma tion of the unusual trans adducts 53, have been explained by the facts that (i) Diels-Alder reactions under atmospheric pressure are thermodynamically controlled, and (ii) the anti-endo adducts 52 are converted into the short-lived syn-endo adducts 54 which tautomerize (via a dienol or its aluminum complexes) to 53. The formation of trans compounds 53 by induced post-cycloaddition isomerization makes the method more flexible and therefore more useful in organic synthesis. 

The synthesis of chaparrinone and other quassinoids (naturally occurring substances with antileukemic activity) is another striking example [16a-c]. The key step of synthesis was the Diels-Alder reaction between the a,/l-unsaturated ketoaldehyde 1 (Scheme 6.1) with ethyl 4-methyl-3,5-hexadienoate 2 (R = Et). In benzene, the exo adduct is prevalent but it does not have the desired stereochemistry at C-14. In water, the reaction rate nearly doubles and both the reaction yield and the endo adduct increase considerably. By using the diene acid 2 (R = H) the reaction in water is 10 times faster than in organic solvent and the diastereoselectivity and the yield are satisfactory. The best result was obtained with diene sodium carboxylate 2 (R = Na) when the reaction is conducted 2m in diene the reaction is complete in 5h and the endo adduct is 75% of the diaster-eoisomeric reaction mixture. 

The cycloaddition of glyoxylic acid with cyclopentadiene in water at pH 6 and 60 °C is slow and occurs with low yield and low diastereoselectivity [18] (Scheme 6.17). Proton (pH = 0.9) [18], copper salts [27] and Bi(OTf)3 [28] accelerate the reaction and increase the diastereoselectivity. The lactones 28 and 29 originate from endo and exo cycloadducts 27, respectively. The proposed rearrangement is depicted in Scheme 6.17 for the major endo adduct 30. A competitive ene reaction that originates 28 and 29 cannot be excluded [28]. 

The Diels-Alder reaction of methyl methacrylate with cyclopentadiene was studied [72] with solutions from three different regions of the pseudophase diagram for toluene, water and 2-propanol, in the absence and in the presence of surfactant [sodium dodecyl sulfate (SDS) and hexadecyltrimethylammonium bromide (HTAB)]. The composition of the three solutions (Table 6.11) corresponds to a W/O-fiE (A), a solution of small aggregates (B) and a normal ternary solution (C). The diastereoselectivity was practically constant in the absence and in the presence of surfactant a slight increase of endo adduct was observed in the C medium in the presence of surfactant. This suggests that the reaction probably occurs in the interphase and that the transition state has a similar environment in all three media. 

Secondary orbital interactions (SOI) (Fig. 2) [5] between the non-reacting centers have been proposed to determine selectivities. For example, cyclopentadiene undergoes a cycloaddition reaction with acrolein 1 at 25 °C to give a norbomene derivative (Fig. 2a) [6]. The endo adduct (74.4%) was preferred over the exo adduct (25.6%). This endo selectivity has been interpreted in terms of the in-phase relation between the HOMO of the diene at the 2-position and the LUMO at the carbonyl carbon in the case of the endo approach (Fig. 2c). An unfavorable SOI (Fig. 2d) has also been reported for the cycloaddition of cyclopentadiene and acetylenic aldehyde 2 and its derivatives (Fig. 2b) [7-9]. The exo-TS has been proposed to be favored over the endo- IS. 

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